{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T20:14:41Z","timestamp":1762460081395,"version":"build-2065373602"},"reference-count":67,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T00:00:00Z","timestamp":1645660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003107","name":"Federal Ministry of Health","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/501100003107","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Freie und Hansestadt Hamburg","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The human adenovirus type C5 (HAdV-C5) E1B-55K protein is a multifunctional regulator of HAdV-C5 replication, participating in many processes required for maximal virus production. Its multifunctional properties are primarily regulated by post-translational modifications (PTMs). The most influential E1B-55K PTMs are phosphorylation at highly conserved serine and threonine residues at the C-terminus, and SUMO conjugation to lysines 104 (K104) and 101 (K101) situated in the N-terminal region of the protein, which have been shown to regulate each other. Reversible SUMO conjugation provides a molecular switch that controls key functions of the viral protein, including intracellular trafficking and viral immune evasion. Interestingly, SUMOylation at SUMO conjugation site (SCS) K104 is negatively regulated by another multifunctional HAdV-C5 protein, E4orf6, which is known to form a complex with E1B-55K. To further evaluate the role of E4orf6 in the regulation of SUMO conjugation to E1B-55K, we analyzed different virus mutants expressing E1B-55K proteins with amino acid exchanges in both SCS (K101 and K104) in the presence or absence of E4orf6. We could exclude phosphorylation as factor for E4orf6-mediated reduction of E1B-55K SUMOylation. In fact, we demonstrate that a direct interaction between E1B-55K and E4orf6 is required to reduce E1B-55K SUMOylation. Additionally, we show that an E4orf6-mediated decrease of SUMO conjugation to K101 and K104 result in impaired co-localization of E1B-55K and SUMO in viral replication compartments. These findings indicate that E4orf6 inhibits E1B-55K SUMOylation, which could favor assembly of E4orf6-dependent E3 ubiquitin ligase complexes that are known to degrade a variety of host restriction factors by proteasomal degradation and, thereby, promote viral replication.<\/jats:p>","DOI":"10.3390\/v14030463","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T21:11:52Z","timestamp":1645737112000},"page":"463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Protein\u2013Protein Interactions Facilitate E4orf6-Dependent Regulation of E1B-55K SUMOylation in HAdV-C5 Infection"],"prefix":"10.3390","volume":"14","author":[{"given":"Marie","family":"Fiedler","sequence":"first","affiliation":[{"name":"Department of Viral Transformation, Leibniz Institute for Experimental Virology (HPI), 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5367-1401","authenticated-orcid":false,"given":"Wing-Hang","family":"Ip","sequence":"additional","affiliation":[{"name":"Department of Viral Transformation, Leibniz Institute for Experimental Virology (HPI), 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helga","family":"Hofmann-Sieber","sequence":"additional","affiliation":[{"name":"Department of Viral Transformation, Leibniz Institute for Experimental Virology (HPI), 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britta","family":"Wilkens","sequence":"additional","affiliation":[{"name":"Department of Viral Transformation, Leibniz Institute for Experimental Virology (HPI), 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francis K.","family":"Nkrumah","sequence":"additional","affiliation":[{"name":"Department of Viral Transformation, Leibniz Institute for Experimental Virology (HPI), 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Institute of Virology and Microbiology, Witten\/Herdecke University, 58453 Witten, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Ehrhardt","sequence":"additional","affiliation":[{"name":"Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Institute of Virology and Microbiology, Witten\/Herdecke University, 58453 Witten, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0698-5395","authenticated-orcid":false,"given":"Luca D.","family":"Bertzbach","sequence":"additional","affiliation":[{"name":"Department of Viral Transformation, Leibniz Institute for Experimental Virology (HPI), 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Dobner","sequence":"additional","affiliation":[{"name":"Department of Viral Transformation, Leibniz Institute for Experimental Virology (HPI), 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1126\/science.137.3533.835","article-title":"The quest for human cancer viruses: A new approach to an old problem reveals cancer induction in hamsters by human adenovirus","volume":"137","author":"Trentin","year":"1962","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0092-8674(77)90180-5","article-title":"An amazing sequence arrangement at the 5\u2032 ends of adenovirus 2 messenger RNA","volume":"12","author":"Chow","year":"1977","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1073\/pnas.74.8.3171","article-title":"Spliced segments at the 5\u2019 terminus of adenovirus 2 late mRNA","volume":"74","author":"Berget","year":"1977","journal-title":"Proc. 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